1. Field of the Invention
This invention relates to a method and apparatus for in-process, automated analysis using a modified form of Isotope Dilution Mass Spectrometry (IDMS). More specifically, the method is an elemental and speciation threshold measurement method that is optimized for quality assurance at and near instrumental detection limits. The threshold measurement method is automated and may be employed for unattended operation of an In-process, Atmospheric Pressure Interface, Mass Spectrometer (IP-API-MS). The IP-API-MS apparatus is designed for identification and quantification of elemental contaminants or compounds and species in fluids.
2. Description of the Prior Art
It has been known to employ mass spectrometry instrumentation in measuring parts per billion (ppb) is frequently used as the technique of choice in measuring ppb and sub-ppb levels of elements or compounds in aqueous and other solutions as well as in gases. Mass spectrometers are typically operated and regularly calibrated by experienced technicians. In many cases, however, unattended operation of the mass spectrometer is desired. These cases may include remote operation, around the clock monitoring, or operation either in hostile environments, or where human interaction must be minimized. One such case is that of contamination monitoring and control in the wet process baths, such as, for example, the semiconductor industry which requires a clean room environment where minimal human interaction is desired. Installation of real time, in-situ, sensors into clean room process is a major defect reduction challenge in the industry. International Technology Roadmap for semiconductors 1999 Edition: Defect Reduction, Sematech, Austin Tex., (pg. 270) (1999).
In order to accomplish unattended operation, the method should automatically monitor elemental concentrations at their threshold level, accurately and without the need to compensate for the inevitable systematic errors associated with instrument drift. Quantitation of elemental concentrations may then be obtained without the need for traditional calibration once the threshold level has been exceeded. Traditional calibration techniques use calibration standards to generate a calibration curve which relates instrument response to concentration of standards. The calibration curve is used in order to determine the concentration of unknown sample. A typical calibration curve is illustrated in FIG. 1 (curve A). Traditional techniques will not yield accurate results if the instrument response drifts or there is a response shift caused by a difference in the matrices between the standard and the sample. Mass spectrometers are especially susceptible to rapid drift causing a change in the calibration response as shown in FIG. 1 (curve B). This rapid drift results in the need for frequent recalibrations that are normally performed by experienced technicians. The effort of matching the matrices of the sample and standard must be made in order to insure ionization efficiencies, ionization suppression or enhancements remain identical between sample and standard.
Viscosity differences between the sample and standard matrices may also cause unequal instrument responses associated with changing sample introduction rates which are inevitable in real world situations. Matrix effects altering solution viscosity or ionization efficiency can result in calibration changes such as shown in FIG. 1 (curve C). The present invention uses modification of IDMS in order to achieve measurements that are optimized for quality assurance at and near instrumental detection limits without the need for traditional calibration.
IDMS is based upon the addition of an enriched isotope standard to a sample to be analyzed. See, generally, U.S. Pat. No. 5,414,259 the disclosure of which is expressly incorporated herein by reference. After equilibration of the sample and standard, the natural isotopic ratio of the sample will have been altered by the enriched standard and the new isotopic ratio is measured by a mass spectrometer. If the concentration of an enriched isotopic standard is known, as well as the enriched isotopic ratio, then the measured ratio of altered natural elemental isotopes provides the elemental concentration of the sample. This method has only a very few well-defined possibilities for error. Each of these possibilities can be calibrated and eliminated, leaving the uncertainty in ratio determination of the two isotopes as the final error for the measurement. This uncertainty is based on the mass spectrometer""s ability to make this isotopic ratio measurement. If the enriched isotope standard of known concentration is introduced, in a precisely controlled fashion, to the sample on-line, all normal interferences are eliminated for each element or species being measured. As only the altered isotope ratio is needed to obtain the concentration of the sample, the physical and chemical differences of flow rate and ionization efficiencies are essentially eliminated. Therefore, IDMS is an ultimate correction technique for both long-term and short-term instrument drift, as well as countering non-spectroscopic interference. This procedure, in general, provides accurate detection for the instrument and process necessary for quality control in ultra-trace analysis. In addition, traditional IDMS has been employed primarily with both Inductively Coupled Plasma Mass Spectrometers (ICP-MS) and Thermal Ionization Mass Spectrometers (TIMS). Both ICP-MS and TIMS instrumentation are not deemed suitable for operation in an unattended mode. Fassett, J. D., Paulsen, P. J. Isotope-dilution mass spectrometry for accurate elemental analysis, Anal. Chem. (1989) 61 643A-649A; Rottmann, L., Heumann, K. G., Development of an on-line Isotope Dilution Technique with HPLC/ICP-MS for the accurate determination of elemental species. Fresenius J. Anal. Chem., (1994) 350 221-227; Rottmann, L., Heumann, K. G., Determination of Heavy Metal Interactions with Dissolved Organic Materials in Natural Aquatic Systems by Coupling High-Performance Liquid Chromatography System with an Inductively Coupled Plasma Mass Spectrometer. Anal. Chem., (1994) 66, 3709-3715; Heumann, K. G., Rottmann, L., Vogl, J., Elemental Speciation with Liquid Chromatography-Inductively Coupled Plasma Isotope Dilution Mass Spectrometry. J. Anal. Atom. Spectro. (1994) 9 1351-1355; Horn, M., Heumann, K. G., Comparison of Heavy Metal Analysis in Hydrofluoric Acid used in Microelectronic Industry by ICP-MS and Thermal Ionization Isotope Dilution Mass Spectrometry, Fresenius J. Anal. Chem., (1994) 350 286-292.
A method of using on-line IDMS as an internal standard with an ICP-MS instrument has been suggested with an enriched isotopic standard being continuously introduced into the sample stream and mixed (allowed to equilibrate) prior to introduction into an ICP-MS instrument. Rottmann, L., Heumann, K. G., Development of an on-line Isotope Dilution Technique with HPLC/ICP-MS for the accurate determination of elemental species. Fresenius J. Anal. Chem., (1994) 350 221-227; Rottmann, L., Heumann, K. G., Determination of Heavy Metal Interactions with Dissolved Organic Materials in Natural Aquatic Systems by Coupling High-Performance Liquid Chromatography System with an Inductively Coupled Plasma Mass Spectrometer. Anal. Chem., (1994) 66, 3709-3715; Heumann, K. G., Rottmann, L., Vogl, J., Elemental Speciation with Liquid Chromatography-Inductively Coupled Plasma Isotope Dilution Mass Spectrometry. J. Anal. Atom. Spectro. (1994) 9 1351-1355. An on-line HPLC/ICP-IDMS method for elemental speciation was tested. In the case published, heavy metals in humic complexes found in natural waters were measured using a High Resolution ICP-MS with either an iron, copper, or a molybdenum enriched spike introduced as the IDMS calibration standard. Selection of which element standard was contingent upon the element to be analyzed in the sample. Rottmann, L., Heumann, K. G., Development of an on-line Isotope Dilution Technique with HPLC/ICP-MS for the accurate determination of elemental species. Fresenius J. Anal. Chem., (1994) 350 221-227; Rottmann, L., Heumann, K. G., Determination of Heavy Metal Interactions with Dissolved Organic Materials in Natural Aquatic Systems by Coupling High-Performance Liquid Chromatography System with an Inductively Coupled Plasma Mass Spectrometer. Anal. Chem., (1994) 66, 3709-3715; Heumann, K. G., Rottmann, L., Vogl, J., Elemental Speciation with Liquid Chromatography-Inductively Coupled Plasma Isotope Dilution Mass Spectrometry. J. Anal. Atom. Spectro. (1994) 9 1351-1355. It was stated that xe2x80x9cquantitative chromatographic separation of the species to be analyzedxe2x80x9d is one of the preconditions for this method and xe2x80x9cquantitative separation is essential before the spiking step takes place (for a species-unspecific spike).xe2x80x9d It was also stated that xe2x80x9c(for a species-unspecific spike), equilibration between the separated species and spike must be guaranteed . . . by high temperature of the argon plasma (in ICP-MS).xe2x80x9d Rottmann, L., Heumann, K. G., Development of an on-line Isotope Dilution Technique with HPLC/ICP-MS for the accurate determination of elemental species. Fresenius J. Anal. Chem., (1994) 350 221-227. HPLC separation and ICP-MS measurement are two essential parts of their method.
Semiconductor manufacturers rely on the purity of chemicals to create sub-micron devices from silicon wafers. Impure chemicals tend to result in devices that will not work. It is, therefore, important to know whether a wet chemical is, in fact, pure, or adequately pure. Current methods of determining purity tend to be expensive, slow, off-line chemical analyzers. This problem becomes enhanced with continued device shrinkage as in the move to 300-mm wafers and copper interconnects. Captive and contract analytical laboratories tend to produce chemical assays and time frames ranging from 24 to 72 hours. One of the consequences of this lack of timely information is the failure to know when to dispose of these expensive chemicals.
It has been suggested to employ in-line ICP-MS in a method of monitoring concentration of metals in silicon wafer cleaning baths. See Using ICP-MS for in-line monitoring of metallics in silicon wafer cleaning baths  less than http://www.micromagazine.com/archive/99/02/shive.html greater than  (February1999)
Isotope dilution Mass Spectrometry for ultra-trace analysis has been previously known. Fassett, J. D. and Kingston, H. M., Determination of Nanogram Quantities of Vanadium in Biological Material by Isotope Dilution Thermal Ionization Mass Spectrometry With Ion Counting Detection, Anal. Chem., (1985) 57 2474-2478. In this publication ultra-trace analysis uses IDMS in the traditional way with isotopically enriched spikes in batch spiked standards. These isotopes are spiked into low concentration samples and blanks and any species information is removed using the batch sample method. Complete transformation of all species is traditionally a prerequisite to most IDMS protocols to prevent multiple species existing in the sample simultaneously. In addition, this transformation prevents the spiked isotopes and the sample isotopes from existing in different species form. As a result, elemental species determinations and evaluations providing both are not possible and are in fact prevented by the traditional IDMS technique.
U.S. Pat. No. 5,012,052 discloses a patent by Hayes describes a method for isotope monitoring for gas that is an on-line continuous combustion from organic components to assist in the determination of the origin of objects based on the C-12 and C-14 ratios. This method requires a combination of gas chromatograph and flame ionization detector (FID), and palladium separator and oxygen charged combustion reactor prior to mass spectrometry. The method requires the use of the combustion chamber, and a palladium separator prior to the mass spectrometer. The goal of this method and instrument is comparison with an isotopic standard to establish isotopic ratios for carbon for origin identification of gases specifically using C-12 and C-14. There is no attempt to perform trace analysis of transition or other metals and quantification is not based on isotope dilution measurements. This method will not work for metals.
U.S. Pat. No. 5,572,024 discloses method and apparatus for quieting the introduction into a mass spectrometer from inductively coupled plasma (ICP) devise by manipulating skimmer cone diameters and pressure. The invention is an improvement of ratio precision measurements over well known ICP-MS and MIP-MS (microwave induced plasma) technology. It describes modifications to a mass spectrometer inlet that enables more precise measurement of isotopes. It requires a plasma device and also reduces the sensitivity of the mass spectrometer.
U.S. Pat. No. 5,872,357 discloses a series of calibrant compositions for organic compounds that enable calibration across a broad mass spectral range for electrospray mass spectrometry, as well a method of using these organic calibrant compositions to calibrate a mass spectrometer. The invention provides a class of new organically based calibrant compositions and limits its application to the usage of these calibrant compositions.
U.S. Pat. No. 6,032,513 discloses a hollow electrode for the improvement of ionization in an atmospheric-pressure ionization source and substitute a more easily ionized carrier gas for the sample gas stream. The disclosure is specific for gas analysis and requires the substitution of the gas stream and the use of a hollow electrode prior to a mass spectrometric measurement. This technology is not applicable in the isotopically based measurements that are the focus of the present invention.
IDMS using Flow Injection Analysis (FIA) introduction to an ICP-MS has been known. Viezian, Miklos; Alexandra Lasztity, Zioaru Wang and Ramon M. Barnes, On-Line Isotope Dilution and Sample Dilution by Flow Injection and Inductively Coupled Plasma Mass Spectrometry, J. Anal. Atom. Spectro., (1990) 5 125-133. This technique uses FIA to mix the isotopically enriched spike and the sample prior to introduction to the ICP-MS. The spike and sample are injected simultaneously to form a zone within a neutral carrier liquid prior to introduction to the ICP-MS. The volume of a fixed sample loop controls the amounts of spike and sample. Physical mixing of the two solutions occurs between the confluence point and the nebulizer. As in traditional IDMS methods species information is unavailable, as the enriched spike is species-unspecific. In addition, the technique suggested on-line dilution using an inert reagent; a technique that is easily accomplished using FIA.
An automated calibrant apparatus was disclosed in U.S. Pat. No. 5,703,360. It introduces a standard reference solution automatically into a mass spectrometer ESI or Atmospheric Pressure Chemical Ionization (APCI) to calibrate or tune the mass spectrometer. In this patent a switching valve is used to introduce the standard as desired to the ESI or APCI. As the standard reference solution and the sample solution are from different sources matrix effects are not eliminated.
U.S. Pat. No. 5,703,360 discloses that one or two traditional standard reference solutions can be used to tune the mass spectrometer with respect to the mass axis, and to assess the functionality of the instrument and to re-calibration the instrument. This technique of introducing two sequential calibration standards will not eliminate the short or long-term drift that can be a problem in unattended operation of a mass spectrometers. See U.S. Pat. No. 5,703,360.
Atmosphere pressure ionization (API) techniques includes electrospray (ES) ionization and atmosphere pressure chemical ionization (APCI). This technique has been widely used to characterize bio-molecules such as peptides, proteins, nucleic acids and carbohydrates. Cole, R. B. Electrospray Ionization Mass Spectrometry: Fundamentals Instrumentation and Applications; John Wiley and Sons, Inc.: New York, 1997. It is also used to qualitatively determine the presence of inorganic, organometallic and complexed metal ions, but quantifying that information has remained a significant challenge. High background due to chemical noise and signal suppression (matrix effects) appear to be the uppermost limiting factors for the quantification of most analytes. Stewart, I. I., Electrospray Mass Spectrometry: a Tool for Elemental Speciation, Spectrochim. Acta. Part-B. (1999) 54B 1649-1695. Collision-induced dissociation (CID) generates energetic collisions and can simplify mass spectra, reduce the background and increase the sensitivity. However, stable operation is limited to a narrow range of solution conductivities and can cause inherent non-linearity signal response during the quantification.
Speciated Isotope Dilution Mass Spectrometry (SIDMS) has been developed to assess the quantification of species and also their transformations. See U.S. Pat. No. 5,414,259. In SIDMS a predetermined species is specifically isotopically labeled and introduced to accomplish these measurements. The species of interest is previously known and specifically evaluated.
In summary, a method and associated apparatus have been developed to accomplish unattended operation of an apparatus that will automatically and accurately monitor elemental concentration threshold levels, identify, and quantify elemental contaminants or compounds and species in fluids.
The present invention employs modifications of traditional IDMS methods that enhance and improve measurement at and near the detection limit of mass spectrometers. These modifications provided for quality assurance of both ultra trace elemental and speciated measurements.
The method and apparatus of this invention is preferably to be used with an IP-API-MS instrument instead of an ICP-MS. Neither HPLC nor ICP-MS is an essential instrumentation in the IP-API-MS apparatus. In the present method, no chromatographic separation is required. The equilibrium between spike and sample species is achieved by dynamical pretreatment, which may be complex, oxidation, or other, of both sample and spike to transform them to the same species before pre-concentration and determination.
In the present invention the labeled species (frequently multiple species simultaneously) are being created in solution and are not previously determined in composition and structure until evaluated for structural information. Quantification is of the elemental ion and speciation information first established in-process through dynamic equilibrium established with a non-complexing salt of an enriched stable isotope in real time and in-process. The methods provide dynamic labeling and duality of mass spectrometer. Additionally, simultaneous species may be evaluated without separation in one embodiment and sequentially in another. The dynamics and sequences are very different from known methods.
Unlike traditional IDMS this method enhances and improves measurement at and near the detection limit of mass spectrometers. An apparatus has been developed to use the method for In-process measurement, using an Atmospheric Pressure Interface coupled to a Mass Spectrometer (IP-API-MS). The IP-API-MS apparatus is designed for identification and quantification of elemental contaminants or compounds and species in fluids without reliance upon the high temperature argon plasma for equilibrium or requiring a HPLC separation step prior to measurement.
This invention provides a method and apparatus for a fluid (liquid and gas) handling in-process, mass spectrometer (IP-MS) that uses optimized stable isotopic ratios for in-process automated and unattended operation. Both qualitative and quantitative analysis of ultra-trace elements and species information is available. The method uses a mass spectrometer interface that is an Atmospheric Pressure Ionization (API) system that permits species information and quantitative elemental evaluation. The fluid handling system mixes the separated isotopes in a non-ligand form or a highly exchangeable ligand form. The stable enriched isotopes may be optimized for ratio measurement at and near the apparatus detection limit permitting efficient threshold monitoring and quantitative evaluation.
In one embodiment of the invention, the method and apparatus enables the IP-MS to be operated in an unattended manner that is a substantial departure from attended operation protocol where operator calibration and analysis are typically performed. Direct comparison against a calibration curve is unnecessary through the use of ratio measurements. This is a departure from traditional instrument operation where concentrations of elements are made in comparison and where instrument drift requires frequent re-calibration required for quantitation. The ratio is optimized for accuracy and quality assurance at and near the detection limits of the measurement.
In another embodiment of the invention, the method and apparatus enables the IP-MS to enhance the quantitative evaluation of the concentrations at or near detection limits by optimizing the enriched isotope ratio used to spike the sample. This method permits an optimum isotopic ratio at and near the limit of detection that definitively establishes the threshold of detection and the uncertainty of the measurement. The optimization of the ratio for detection limit and near detection limit are achieved by mixing both natural and multiple enriched isotopes in selected quantities of the same element. This improves traditional IDMS methods wherein this measurement is uncertain over a very wide range.
In yet another embodiment of the invention, the method and apparatus quantifies elements without speciation information by mixing known enriched isotopes of elements in a semi-continuous process with the in-process sample stream from the chemical solutions being evaluated. The ionization voltage is purposefully set atypically high enough to eliminate species information directly at the source of the mass spectrometer to optimize the elemental quantitation.
In a further aspect of the invention, the method and apparatus mixes non-ligand bound or weakly ligand optimized enriched isotopes allowing for species transformations of the enriched isotopes into the dominant species set by the chemistry of the reagent streams being interrogated. These species are then directly evaluated using very low voltage and softer ionization conditions preserving the species information of the sample solutions using the same apparatus automatically controlled in alternate methods.
In an additional aspect of the invention, the method and apparatus uses additional solution manipulation after introduction of the stable optimized isotopes to alter the chemical species to permit optimum ionization for maximum sensitivity and detection limits. Other solution manipulations may be performed to change the matrix of the fluid to permit optimum ionization for maximum sensitivity and detection limits.
In yet another aspect of the invention, the method and apparatus mixes the optimized stable isotopes with the sample and the resulting solution is separated or pre-concentrated by element and/or species for sequential evaluation, optimization and maximum sensitivity.
In one preferred embodiment of the invention, the method of automated isotope dilution mass spectrometry includes providing a sample to be analyzed, spiking multiple enriched stable iostopes of elements or species related to the sample and effecting equilibration therebetween. The equilibrated spikes and sample are then subjected to atmospheric pressure ionization with the ions subsequently being introduced into a mass spectrometer for isotopic ratio determination and delivery of the information from the determination to a microprocessor which in turn through a controller effects control of operation of the methods. Information is also delivered from the microprocessor to the system being monitored.
In a particular use, wherein contaminant levels may be monitored at the ultra-trace level in baths employed in the semiconductor industry, in the cleaning of wafers an early warning or alarm may be sounded responsive to a contamination level approaching an upper tolerable limit in the case of warning or reaching or exceeding the same in the case of an alarm.
Corresponding apparatus is provided.
It is an object of the present invention to provide a method and apparatus for in-process automated analysis employing a modified form of Isotope Dilution Mass Spectrometry.
It is yet another object of the present invention to provide such a system which is adapted for automatic and unattended operation.
It is yet another object of the present invention to provide such a method and apparatus for qualitative and quantitative identification of elemental contaminants or compounds and species in fluids.
It is a further object of the present invention to provide such a system which is adapted to be employed in line and to provide a reliable sensitive system not requiring highly skilled personnel for the operation of the same.
It is a further object of the present invention to provide such a system for unattended operation wherein operator calibration and analysis and direct comparison against a calibration curve is not required.
It is a further object of the present invention to employ isotopic ratio determinations that tend to minimize or eliminate instrument stability parameters as sources of error in quantitative measurement.
It is a further object of the present invention to provide such a system which may be operated in one mode to quantified analysis of a species or element and, in another mode, to provide solely relative analysis of the same.
It is an object of the present invention to provide a fully automated, comprehensive, analytical chemistry tool that in rapid and accurate fashion will determine whether a wet bath is contaminated and thereby minimize expensive, reduced yields due to such contamination.
It is a further object of the present invention to provide such a system which is usable in clean rooms having silicon wafer baths and to extend the lives of expensive reagents used in such baths.
It is a further object of the present invention to provide such a system which can provide reliable assays in an automated fashion a number of times per hour.
It is a further object of the present invention to provide such a system which is adapted to accurately and rapidly detect ultra-trace quantities of a specie within a fluid employing isotopic ratio determinations.